Progression of anal neoplasia is common among gay men with HIV

Nearly 40%
of HIV-positive men with low-grade anal neoplasia may progress to high-grade
neoplasia or anal cancer, according to a Spanish study presented on Wednesday at
the 52nd Interscience Conference on Antimicrobial Agents and
Chemotherapy (ICAAC) in San Francisco. Younger age and shorter duration of HIV
infection were risk factors for worsening disease.

Anal cancer
caused by human papillomavirus (HPV) is more common among HIV-positive gay men,
compared with the general population. While AIDS-defining cancers have declined
since the advent of effective combination antiretroviral therapy, some studies
indicate that anal cancer has become more common as people with HIV live
longer.

HPV triggers
abnormal cell growth including warts and neoplasia. Certain 'high-risk' or oncogenic
types – in
particular HPV-16 and HPV-18 – are the usual cause of anal and cervical cancer. But
oncogenic HPV infection does not always result in tissue abnormalities, mild or
low-grade dysplasia (abnormal tissue) does not always progress to more severe or
high-grade neoplasia, and high-grade neoplasia does not always lead to cancer.

Carmen
Hidalgo from Hospital Universitario Virgen de las Nieves in Granada, Spain, and
colleagues looked at predictors of progression from low-grade anal
intraepithelial neoplasia (AIN) to high-grade AIN or anal carcinoma in situ
(localised cancer). They also evaluated the role of different screening methods
for detecting high-grade AIN or anal cancer.

This prospective
cohort study included 163 HIV-positive men who have sex with men seen at the
hospital between April 2010 and April 2012 who participated in an anal neoplasia
screening program.

The participants'
average age was 36 years and they had been diagnosed with HIV for a median of
54 months. They reported a median of one sexual partner during the past year and
nearly 75% said they used condoms. Only 3% were co-infected with hepatitis B or
C. Half were smokers.

Participants
had well-preserved immune function, with a current median CD4 cell count of
about 600 cells/mm3 and a nadir (lowest-ever) count of 375 cells/mm3.
Three-quarters were on antiretroviral therapy and 85% had an undetectable HIV
viral load.

The men
underwent baseline and follow-up evaluations that included anal cytology tests
(examination of a cell sample under a microscope, better known as a Pap smear),
PCR tests for HPV and anoscopy (visual examination using a lighted magnifying
instrument, with application of vinegar to make lesions turn white).

PCR testing
showed that 81% of participants had HPV infection; 68% had high-risk HPV types,
69% had low-risk types and 47% had both. The most common types were HPV-16
(26%); HPV-53 and HPV-6 (15% for both); and HPV-11, HPV-18 and HPV-51 (14% for
each).

About
two-thirds of participants received cytology tests by the time of data
analysis. Within this group, 71% were classified as having modest cell
abnormalities (referred to as low-grade squamous intraepithelial lesions, or
LSIL), 3% had serious abnormalities (high-grade squamous intraepithelial lesions,
or HSIL) and 27% had atypical squamous cells of
undetermined significance (ASCUS).

Half of the
participants underwent anoscopy by the time of analysis. Of these, 28% were
normal, 47% were classified as having low-grade AIN (sometimes referred to as
grade 1, as neoplasia staging terminology is not consistent), 17% were
classified as having high-grade AIN (sometimes called grade 2/3) and 8% had
anal cancer in situ.

The
researchers calculated incidence rates of 14.9 cases per 1000 patient-months
over a median of eleven months for high-grade AIN and 3.3 cases per 1000
patient-months for anal cancer.

Participants
diagnosed with low-grade AIN received annual check-ups, and half had completed
follow-up at the time of analysis. Follow-up anoscopies over a median of eleven
months revealed that 33% progressed from low-grade to high-grade AIN, for a
progression rate of 14.3 per 1000 patient-months. In addition, 5% progressed
from low-grade AIN to anal cancer, a progression rate of 2.0 per 1000
patient-months. Hidalgo did not report how many people experienced regression
or improvement of neoplasia.

The only two
factors significantly associated with progression of low-grade to high-grade AIN
or anal cancer were younger age and shorter time since HIV diagnosis.
Progressors had an average age of 29.5 years compared with 34.1 years for
non-progressors. Intervals since HIV diagnosis were 44 and 60 months,
respectively.

Other analysed
factors – including
AIDS stage, HIV viral load, baseline and nadir CD4 count, use of antiretroviral
therapy, HPV types, number of sexual partners, presence of other sexually
transmitted infections, alcohol use and smoking – were not found to be independent predictors
of progression.

This finding
conflicts with previous studies that have seen a link between anal neoplasia
and several of these factors, in particular HPV type and degree of immune
deficiency. However, only 21 people with low-grade AIN completed follow-up and
small samples sizes make it more difficult to demonstrate statistical
significance.

Turning to
the accuracy of screening methods, the researchers found that the sensitivity,
or ability to identify true cases, of anal cytology alone for detecting
high-grade AIN or anal carcinoma in situ was 80%, high-risk HPV testing was 93%
and the two tests combined reached 100%. Positive predictive values were 18%, 22%
and 19%, respectively.

Specificity,
or ability to rule out false cases, was 34% for cytology alone, 23% for HPV
testing alone and 8% for the two together. Negative predictive values were 90,
93 and 100%, respectively.

Combining
the two tests was also highly accurate for diagnosing any degree of anal
dysplasia, with a sensitivity of 98% and a negative predictive value of 80%.

Anal
cytology and high-risk HPV testing together have good sensitivity and negative
predictive value, the researchers said, concluding that if both tests are
normal, a patient can be presumed not have neoplasia, allowing them to avoid
unnecessary anoscopy.

Offering a different opinion at an
ICAAC 'meet-the-experts' session earlier in the week, Joel Palefsky from the
University of California at San Francisco recommended that all HIV-positive gay
and bisexual men over age 30 should be screened for anal neoplasia using both
cytology testing and digital-rectal examination.

Some abnormalities that do not
show up on a Pap smear may be felt by a manual exam and vice-versa, he
explained. HPV testing may be less useful because its prevalence in this
population is "almost 100%".

Palefsky added that in his
opinion an individual with any degree of abnormality should be followed up with
anoscopy, not just those with suspected high-grade neoplasia. He acknowledged,
however, that cost and limited "people power" can make this difficult
to put into practice.

Reference

Hidalgo Tenorio C et al. Risk factors in the progression of low grade
intraepithelial neoplasia (LGAIN) to high grade intraepithelial neoplasia
(HGAIN) in a cohort of HIV-MSM.52nd
Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco,
abstract H-1921, 2012. View
the abstract on the conference website.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

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NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member
of your healthcare team for advice tailored to your situation.